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Negative epistasis between the malaria-protective effects of α+-thalassemia and the sickle cell trait


The hemoglobinopathies, disorders of hemoglobin structure and production, protect against death from malaria1. In sub-Saharan Africa, two such conditions occur at particularly high frequencies: presence of the structural variant hemoglobin S and α+-thalassemia, a condition characterized by reduced production of the normal α-globin component of hemoglobin. Individually, each is protective against severe Plasmodium falciparum malaria2,3,4, but little is known about their malaria-protective effects when inherited in combination. We investigated this question by studying a population on the coast of Kenya and found that the protection afforded by each condition inherited alone was lost when the two conditions were inherited together, to such a degree that the incidence of both uncomplicated and severe P. falciparum malaria was close to baseline in children heterozygous with respect to the mutation underlying the hemoglobin S variant and homozygous with respect to the mutation underlying α+-thalassemia. Negative epistasis could explain the failure of α+-thalassemia to reach fixation in any population in sub-Saharan Africa.

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Figure 1: IRRs for malaria by hemoglobin type and α+-thalassemia genotype.
Figure 2: The evolutionary consequences of negative epistasis between the malaria-protective effects of HbS and α+-thalassemia.

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We thank the field workers, clinical and medical officers and nursing staff of the Kenya Medical Research Institute Centre for their help with this study and N. Peshu, B. Lowe, N. Alexander and D. Roberts for support and advice. This study received financial support from the Wellcome Trust. T.N.W., R.W.S. and K.M. are supported by the Wellcome Trust. D.J.W. is supported by a grant from the Leverhulme Trust. This paper is dedicated to Steve Bennett. This paper is published with permission from the Director of the Kenya Medical Research Institute.

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Correspondence to Thomas N Williams.

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Williams, T., Mwangi, T., Wambua, S. et al. Negative epistasis between the malaria-protective effects of α+-thalassemia and the sickle cell trait. Nat Genet 37, 1253–1257 (2005).

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